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ALKBH5 通过 mA 依赖性表观遗传沉默 pre-miR-181b-1/YAP 信号轴抑制骨肉瘤的肿瘤进展。

ALKBH5 suppresses tumor progression via an mA-dependent epigenetic silencing of pre-miR-181b-1/YAP signaling axis in osteosarcoma.

机构信息

Department of Orthopedics at The First Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, 150086, Harbin, China.

Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China.

出版信息

Cell Death Dis. 2021 Jan 11;12(1):60. doi: 10.1038/s41419-020-03315-x.

DOI:10.1038/s41419-020-03315-x
PMID:33431791
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7801648/
Abstract

ALKBH5 is the main enzyme for mA-based demethylation of RNAs and it has been implicated in many biological and pathophysiological processes. Here, we aimed to explore the potential involvement of ALKBH5 in osteosarcoma and decipher the underlying cellular/molecular mechanisms. We discovered downregulated levels of demethylase ALKBH5 were correlated with increased mA methylation in osteosarcoma cells/tissues compared with normal osteoblasts cells/tissues. ALKBH5 overexpression significantly suppressed osteosarcoma cell growth, migration, invasion, and trigged cell apoptosis. In contrast, inhibition of ALKBH5 produced the opposite effects. Whereas ALKBH5 silence enhanced mA methylations of pre-miR-181b-1 and YAP-mRNA exerting oncogenic functions in osteosarcoma. Moreover, upregulation of YAP or downregulation of mature miR-181b-5p displayed a remarkable attenuation of anti-tumor activities caused by ALKBH5. Further results revealed that mA methylated pre-miR-181b-1 was subsequently recognized by mA-binding protein YTHDF2 to mediate RNA degradation. However, methylated YAP transcripts were recognized by YTHDF1 to promote its translation. Therefore, ALKBH5-based mA demethylation suppressed osteosarcoma cancer progression through mA-based direct/indirect regulation of YAP. Thus, ALKBH5 overexpression might be considered a new approach of replacement therapy for osteosarcoma treatment.

摘要

ALKBH5 是 mA 基 RNA 去甲基化的主要酶，它与许多生物学和病理生理学过程有关。在这里，我们旨在探讨 ALKBH5 在骨肉瘤中的潜在作用，并阐明其潜在的细胞/分子机制。我们发现与正常成骨细胞/组织相比，骨肉瘤细胞/组织中去甲基酶 ALKBH5 的下调水平与 mA 甲基化的增加相关。ALKBH5 的过表达显著抑制骨肉瘤细胞的生长、迁移、侵袭和触发细胞凋亡。相反，ALKBH5 的抑制产生了相反的效果。而 ALKBH5 的沉默增强了 pre-miR-181b-1 的 mA 甲基化和 YAP-mRNA 的致癌功能，在骨肉瘤中发挥致癌作用。此外，YAP 的上调或成熟 miR-181b-5p 的下调显示出对 ALKBH5 引起的抗肿瘤活性的显著衰减。进一步的结果表明，mA 甲基化的 pre-miR-181b-1 随后被 mA 结合蛋白 YTHDF2 识别，以介导 RNA 降解。然而，甲基化的 YAP 转录本被 YTHDF1 识别，以促进其翻译。因此，基于 ALKBH5 的 mA 去甲基化通过 mA 对 YAP 的直接/间接调控抑制骨肉瘤的癌症进展。因此，ALKBH5 的过表达可能被认为是骨肉瘤治疗的一种新的替代治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/3f170d644321/41419_2020_3315_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/eff1c49c28de/41419_2020_3315_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/1f90971bd4dd/41419_2020_3315_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/2192da58f03d/41419_2020_3315_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/b2fef35a6538/41419_2020_3315_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/448d74f8cc7b/41419_2020_3315_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/75a7ffe48fac/41419_2020_3315_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/1ef69972ed74/41419_2020_3315_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/3f170d644321/41419_2020_3315_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/eff1c49c28de/41419_2020_3315_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/1f90971bd4dd/41419_2020_3315_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/2192da58f03d/41419_2020_3315_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/b2fef35a6538/41419_2020_3315_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/448d74f8cc7b/41419_2020_3315_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/75a7ffe48fac/41419_2020_3315_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/1ef69972ed74/41419_2020_3315_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6464/7801648/3f170d644321/41419_2020_3315_Fig8_HTML.jpg

相似文献

[1]
ALKBH5 suppresses tumor progression via an mA-dependent epigenetic silencing of pre-miR-181b-1/YAP signaling axis in osteosarcoma.

Cell Death Dis. 2021-1-11

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[7]
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引用本文的文献

[1]
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J Transl Med. 2025-8-13

[2]
MARCH8/NSUN6/ROS-mediated DNA damage positive feedback loop regulates cisplatin resistance in osteosarcoma.

Cell Death Differ. 2025-7-19

[3]
Targeting epigenetic regulators as a promising avenue to overcome cancer therapy resistance.

Signal Transduct Target Ther. 2025-7-18

[4]
Reciprocal regulation between m6 A modifications and non-coding RNAs: emerging roles in cancer therapeutic resistance.

Discov Oncol. 2025-5-25

[5]
From bone marrow mesenchymal stem cells to diseases: the crucial role of mA methylation in orthopedics.

Stem Cell Res Ther. 2025-5-6

[6]
ALKBH5 Inhibits YTHDF2-m6A-Mediated Degradation of RCN1 mRNA to Promote Keloid Formation by Activating IRE1α-XBP1-Mediated ER Stress.

J Cosmet Dermatol. 2025-4

[7]
Regulation of Skeletogenic Pathways by m6A RNA Modification: A Comprehensive Review.

Calcif Tissue Int. 2025-4-3

[8]
M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms.

Biomolecules. 2025-1-21

[9]
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Clin Transl Med. 2025-2

[10]
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Med Oncol. 2025-1-24

本文引用的文献

[1]
mA Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

Cancer Cell. 2020-3-16

[2]
MK5 Regulates YAP Stability and Is a Molecular Target in YAP-Driven Cancers.

Cancer Res. 2019-10-2

[3]
The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1.

Biochem Biophys Res Commun. 2019-6-26

[4]
mA mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade.

Nat Commun. 2019-6-25

[5]
YTHDF1 Regulates Tumorigenicity and Cancer Stem Cell-Like Activity in Human Colorectal Carcinoma.

Front Oncol. 2019-5-3

[6]
RNA mA methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail.

Nat Commun. 2019-5-6

[7]
YAP Aggravates Inflammatory Bowel Disease by Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis.

Cell Rep. 2019-4-23

[8]
YAP-independent mechanotransduction drives breast cancer progression.

Nat Commun. 2019-4-23

[9]
Circular RNA circTADA2A promotes osteosarcoma progression and metastasis by sponging miR-203a-3p and regulating CREB3 expression.

Mol Cancer. 2019-4-2

[10]
RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3.

Mol Cancer. 2019-3-28

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